Does this patient have undifferentiated connective tissue disease?

Undifferentiated connective tissue disease (UCTD) is a term suggested by LeRoy 30 years ago to denote autoimmune disease that does not meet criteria for established illnesses such as systemic lupus erythematosus, scleroderma, dermatomyositis, Sjogren's syndrome, vasculitis, or rheumatoid arthritis.

The population generally affected comprises young females, similar to a population of young systemic lupus erythematosus (SLE) patients. It is therefore a challenge to recognize this entity as discreet from, and not simply representing, an early manifestation of one of the above noted groups. Indeed, some 70% of patients defined as having early UCTD will persist with presenting manifestations, while 30% will evolve and be reclassified. While there are no currently accepted criteria defining UCTD from either the American College of Rheumatology (ACR) or the European League Against Rheumatism (EULAR) a number of authors, notably Mosca and Bombardieri have written about this problem over the past decade. They have proposed inclusion as well as exclusion criteria.

The most common presenting manifestations of this syndrome are arthralgia/myalgia, arthritis, Raynaud's phenomenon, sicca syndrome and fatigue. Most authors suggest the patient have a positive ANA to be included within this group. Less commonly encountered findings include urticaria, photosensitivity, mucosal ulcerations, serositis, thyroiditis, cytopenias, and rash.

Other than ANA, serologies for testing serve largely to exclude patients from falling within defined connective tissue disease. Some may predict evolution toward SLE. A sampling of commonly obtained serologies is noted in the next section.

Recent research into undifferentiated connective tissue disease

A literature has developed linking UCTD with idiopathic nonspecific interstitial pneumonia (NSIP). While only 20% of cohorts of UCTD will have pulmonary involvement, a high percentage of patients with idiopathic nonspecific interstitial pneumonia will have UCTD. Recent classification of interstitial lung disease by the American Thoracic Society has separated NSIP from usual interstitial pneumonitis (UIP). The former is manifest with a uniform pattern of cellular infiltrate or fibrosis on biopsy, reticular pattern, traction bronchiectasis or ground glass opacity on high resolution CT and good prognosis (positive response to steroids). UIP, on the other hand, reveals marked fibrosis without significant cellular infiltrate on biopsy, reticular pattern, honeycombing variable traction bronchiectasis on high resolution CT scan (HRCT) and an unfavorable course.

Since Raynaud's is a common feature of both UCTD and defined rheumatic disease (SLE, scleroderma, dermatomyositis and rheumatoid arthritis (RA) there have been efforts to define abnormalities morphologically as well as biochemically in the vasculature of these patients. In one study, scleroderma type loops have been found in a small percentage of UCTD patients (approximately 14%) suggesting increased risk for progression to scleroderma in this group. A second group of patients with primary Raynaud's was followed for almost five years and scleroderma loop pattern was seen antedating progression to scleroderma, dermatomyositis, overlap syndrome with scleroderma and mixed connected tissue disease.

Endothelial dysfunction has also been found in young patients with UCTD manifested by both nitric oxide dependent and independent mechanisms.

Vitamin D and its influence on the immune system has been a topic of increasing interest this past decade. A higher incidence of autoimmunity in patients deficient in vitamin D has been suggested. Patients with UCTD with low vitamin D levels have been reported to have a higher rate of progression to defined connective tissue disease. Recent data suggests some patients with UCTD have overproduction of interferon-γ (T-helper 1 activity) and reduced numbers of regulatory T cells (nTregs). Moreover, treatment with vitamin D (alfacalcidol) was shown to reduce TH1 and TH17 associated cytokine levels and increase numbers of nTregs.

What tests to perform?

Diagnostic testing

The following tests should be considered part of the obligatory evaluation of the patient with presumed autoimmunity. They are ordered at presentation and repeated at intervals predicated on the patient's course but often at yearly intervals in the stable patient to assess disease activity and pattern.

Rheumatoid factor and anti-citrullinated cyclic peptide antibodies (anti-CCP) - while the former may be present in UCTD, the combination of positive rheumatoid factor (RF) and CCP strongly suggests rheumatoid arthritis.

ANA (antinuclear antibody) - this test is considered the basic inclusion denoting autoimmunity. It is now commonly performed on HEp-2 cells and reported by pattern and titer. In UCTD the most common pattern will be speckled or less commonly homogenous. Nucleolar and anti-centromere patterns may denote early scleroderma and peripheral pattern SLE. Titers may be low or robust without special significance.

Anti-DNA antibody - this is commonly seen in SLE and should bias the clinician toward that diagnosis.

Ribonucleoproteins (RNP) - commonly seen in SLE but may persist in UCTD

Anti-histone antibody - should be ordered when drug induced lupus is suspected.

SSA/B (Ro/La) - commonly seen in SLE, sub-acute LE and Sjogren's syndrome but SSA may be present in UCTD, with or without symptomatic sicca phenomena.

Anti-centromere and Scl-70 antibodies - these are highly specific for limited (CREST syndrome) and generalized scleroderma respectively in symptomatic patients. While both may be seen in patients without evidence of scleroderma or in the case of anti-centromere antibody of primary biliary cirrhosis, its presence in association with Raynaud's suggests evolution toward those entities. Isolated anti-Scl-70 is uncommonly observed in the otherwise healthy individual and may not predict evolution to scleroderma.

Anti-cardiolipin antibody and anti-beta 2 glycoprotein antibody panels - these associate with primary antiphospholipid antibody syndrome and with SLE. Antibodies with no, or lesser, pathogenicity may be seen in chronic infections.

Angiotensin converting enzyme - seen in 50% of patients with sarcoidosis, a condition which mimics connective tissue disease both with constitutional symptoms, joint pain and often positive ANA and rheumatoid factor.

Cytopenias - while leucopenia and thrombocytopenia may be seen in UCTD, their presence should bias the observer toward SLE.

Imaging - ask yourself: which imaging studies should I order (discuss them in the order of the information they provide to the physician)? Does the imaging modality matter? How do I interpret imaging results? How often should I order imaging tests. What are the next steps?

Chest X-ray (CXR) should be obtained in all patients to exclude parenchymal disease, i.e., interstitial fibrosis, as well as to exclude adenopathy, which may denote sarcoidosis or lymphoma presenting as a paraneoplastic syndrome.

Other tests may be obtained based upon the patient's specific complaints or findings:

Computed tomography (CT) of chest or pulmonary function tests in patients with symptoms or CXR abnormality. CT may be particularly helpful to define interstitial disease as ground-glass opacity in the case of INIP as opposed to honeycombing seen in usual interstitial pneumonia (UIP).

How should patients with undifferentiated connective tissue disease be managed?

Management of patients with UCTD, similar to patients with SLE, is predicated upon the symptomatic manifestation noted below, or specific finding where treatment has been shown to positively alter outcome. The underlying assumption is that patients will generally have a favorable course.

Positive serology- in the absence of an organ-specific problem, a positive serology alone is not treated.

Arthralgia and arthritis - since for the most part, patients do not have significant synovitis leading to erosive disease, analgesia with acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) may suffice and be prescribed on an "as needed" basis. For more persistent complaint and or frank arthritis (synovitis), NSAID may be supplemented with anti-malarial (chloroquine or hydroxychloroquine) or more potent immunosuppressant (i.e. methotrexate).

Myalgia - as for arthralgia, acetaminophen, NSAID and antimalarials may be used as needed. Myositis though less likely might require steroid or immunosuppressive agent (methotrexate or azathioprine). Myositis would require confirmation by muscle biopsy and likely lead to change in diagnosis from UCTD to either poly or dermatomyositis. For patients with little complaint and borderline elevation of CK, observation may suffice.

Raynaud's - many patients with mild Raynaud's may be treated with hand and foot protection along with prompt warming if an attack develops. Patients with more significant Raynaud's, i.e. those with painful attacks, fissuring of digital pulp or frank ulceration will need treatment. This group usually receives low dose ASA (81mg OD) along with a calcium blocker (e.g. nifedipine xl 30-90mg per day) or alpha blocker (e.g. prazocin 2-10mg per day).

Interstitial lung disease - as noted above, patients may have NSIP an entity with a favorable outcome. Low grade disease may be observed without treatment or patients may receive corticosteroids. Management of this condition will generally be coordinated with pulmonary physicians.

Fatigue and constitutional symptoms - may respond to antimalarials, which are commonly prescribed, and to steroid or immunosuppressants which are largely avoided due to toxicity.

What happens to patients with undifferentiated connective tissue disease?

One way of looking at this problem, is to think of a universe of people exhibiting some degree of autoimmunity. On the simplest level, an individual might have an autoantibody with no other manifestation of disease. Another patient might have an autoantibody and a single complaint without objective inflammation in an end organ. Finally, autoantibodies and complaints coupled with discreet end organ inflammation might allow a diagnosis of a specific connective tissue disease. In this framework, UCTD represents the large population of patients with an autoantibody and few complaints or findings. Immunogenetics coupled with environmental exposure would account for presentation and progression. It is hopeful that correction of hypovitaminosis D or other yet unrecognized states can be affirmatively manipulated and prevent progression to more significant disease.

As previously noted, 70% of patients with UCTD will persist with presenting manifestations and not progress to a defined rheumatic disease. Early in the course, anxiety is a common outcome for patients and family, but time and experience reduces concern. For the smaller group of patients that progress, additional disease manifestations or increasing severity of initial complaints will be dealt with as noted above or in a disease specific fashion (i.e. development of SLE nephritis will require specific protocol). The patient will be monitored for erosive arthritis, muscle weakness and pulmonary dysfunction, but these are generally obvious per the patient's complaint. One issue which remains controversial is whether antimalarials should be prescribed to prevent disease progression. There is some data suggesting that similar to SLE, patients with UCTD may be less likely to progress if treated. Risk of skin pigmentation and retinal toxicity must be weighed against uncertain benefit.

How to utilize team care?

For the patient cared for by a primary physician, referral to a rheumatologist will aid in ensuring evaluation is adequate and with interpretation of abnormal results. Some findings on physical examination, i.e. nail fold capillary microscopy will require some experience to ensure proper identification of abnormal loops. This in turn might indicate scleroderma or dermatomyositis. Other specialty consultations will depend upon observation of nephritis, interstitial lung disease or neurological disease.

A special circumstance in management is the care of the young pregnant female. Two groups recently reviewed their experience and revealed increased pregnancy related complications of a modest degree along with increased risk of evolution toward defined connective tissue disease. Since antibody to SSa is often found in this population, awareness of the potential for developing neonatal heart block is essential and will require involvement of a experienced neonatal cardiologist.